Treatment of migraine headache

ABSTRACT

The invention is directed to pharmaceutical compositions useful in the treatment of migraine. The compositions contain metoclopramide and one or more NSAIDs in unit dosage form. By selecting NSAIDs that are non-acidic or segregating the metoclopramide and NSAID, the storage life of the compositions has been increased. Also disclosed are coordinated dosage forms for the sequential release of drugs. The invention encompasses methods of treating migraine using any of these dosage forms.

REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Ser. No. 08/966,506,filed Nov. 10, 1997 (now U.S. Pat. No. 6,077,539), which is acontinuation-in-part of U.S. application Ser. No. 08/748,332, filed Nov.12, 1996, now abandoned.

FIELD OF THE INVENTION

The present invention is directed to compositions comprisingmetoclopramide and a second drug, particularly an analgesic. Thesecompositions may be used as a treatment for migraine and otherdisorders.

BACKGROUND

Migraine is a painful syndrome characterized by unilateral, pulsatingheadaches, nausea, vomiting, and sensitivity to light and sound.Approximately 23 million Americans presently suffer from this disorder.Drugs that have been used in an attempt to treat migraine include:ergotamine and ergotamine-like agents; serotonin agonists; and caffeinewith ergots or other pharmacologic agents (see e.g., Silberstein, S. D.,Curr. Opinion Neurology 7:258-263 (1994); Welch, K. M. A., New Engl J.Med. 329:1476-1483 (1993); Kumar, K. L., J. Gen. Int. Med. 9:339-348(1994); Saadah, H., Headache 32:95-97 (1992); and Becker,Arzneimittelforshung 42(4):552-555 (1992)). All of these drugs arethought to initially relieve migraine-associated pain by causingvasoconstriction. Unfortunately, this leads to numerous side effectssuch as chest pain or pressure, flushing, generalized tinglingsensations, nausea, vomiting, pain in the legs and arms, asthenia,drowsiness, and dizziness. Acute ergotism is a particularly perniciousside effect of ergot drugs and is characterized by severe central andperipheral vasoconstriction, nausea, vomiting, diarrhea, colic,headache, vertigo, paresthesia, and possibly convulsive seizures.

Patients have, on occasion, found total or partial relief for some formsof migraine through the use of non-prescription analgesics. As outlinedby Welch (New Engl J. Med. 329: 1476-1483 (1993)), the initial dosagesof such analgesics are typically: aspirin, 500-650 mg; acetaminophen,500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and,ibuprofen 200 mg. After oral dosing, peak plasma concentrations innormal subjects usually occur at about 1 hour for aspirin andacetaminophen, and between 1 and 2 hours for naproxen sodium, tolfenamicacid, and ibuprofen. However, the absorption of these and other agentsduring a migraine attack has been shown to be impaired, apparently dueto gastric stasis.

Ideally a migraine drug formulation should be nonaddictive and free ofvasoactive agents (i.e. agents causing the constriction or dilation ofblood vessels). This requires the exclusion of ergots, serotoninagonists such as sumatriptan (including related 5 HT agonistheterocyclic compounds as described in U.S. Pat. No. 4,816,470) andcaffeine. The formulation should relieve pain, reduce gastric stasis,reduce nausea, and allow for a faster rate of drug absorption.

Metoclopramide is a drug known to relieve migraine-associated nauseawhen administered at a minimum oral dose of 10 mg. Poyser et al. havedescribed a formulation in which aspirin is uniformly intermixed withmetoclopramide (U.S. Pat. No. 4,380,540). One drawback of thisformulation is that it undergoes unacceptable degradation in a matter oftwo to three weeks at ambient temperatures. In addition, aspirin isknown to have a very short plasma half life. New formulations ofmetoclopramide that are effective in treating migraine headache and thatavoid the disadvantages of this and other previously disclosedpreparations would represent a clear advance in the art.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery of improvedformulations for the treatment of migraine headache. The formulationscontain a combination of metoclopramide and one or more analgesics(preferably NSAIDs) and are prepared in such a manner as to avoid theloss of activity that has been observed to sometimes accompany suchformulations. In particular, it has been discovered that loss ofactivity occurs when an acidic analgesic is in prolonged contact withmetoclopramide. Thus, compositions that utilize non-acidic analgesics(i.e., analgesics having a pK_(a) of 7 or above when dissolved in water)or in which metoclopramide and analgesic are separated offer substantialadvantages. In addition, new dosage forms have been developed that haveimproved therapeutic characteristics. Specifically, improved absorptionof drug has been accomplished using “coordinated” dosage forms in whichmetoclopramide and NSAID are sequentially delivered. Improvedcharacteristics may also be obtained by using long-acting analgesics oranalgesics that are formulated to be long acting.

In its first aspect, the present invention is directed to apharmaceutical composition in unit dosage form suitable for oraladministration in the treatment of migraine headache. The dosage formcontains metoclopramide in an amount effective to increase gastricmotility in a patient suffering from a migraine attack and a non-acidicanalgesic (preferably a non-acidic NSAID) in an amount effective toreduce or eliminate headache pain. Preferably, the dosage form should beeither a tablet or capsule and should be free from vasoactive agents,including 5 HT agonist vasoactive agents. The dosage form may becoordinated for the sequential delivery of drugs and may incorporatelong-acting NSAIDs, including cyclooxygenase-2 inhibitors.Alternatively, the dosage form may contain analgesics formulated to belong acting. The most preferred non-acidic NSAID is Celecoxib(Celebrex®), typically in an amount of between 25 and 250 mg. It isdesirable that sufficient metoclopramide be present to reduce oreliminate the nausea associated with migraine headache. Typically, adosage form will have between 1 mg and 100 mg of metoclopramide.

In a second aspect, the invention is directed to a pharmaceuticalcomposition in unit dosage form that has been acid-base storagestabilized. Metoclopramide and one or more analgesics (preferablyNSAIDs) are present in an amount such that their combination iseffective in reducing or eliminating headache pain. Acid-base storagestabilization is accomplished by constructing dosage forms in a mannerthat eliminates or minimizes contact between the drugs during storage.For example, tablets or capsules may be made in which eithermetoclopramide or analgesic is barrier coated. Alternatively,metoclopramide and analgesic may be in separate layers of a multilayertablet. Dosage forms should typically be free of vasoactive agents, maybe coordinated and may contain either long-acting NSAIDs or NSAIDsformulated to be long acting. Typical NSAIDs that may be used include:acetaminophen; ibuprofen; flurbiprofen; ketoprofen; naproxen; oxaprozin;etodolac; indomethacin; ketorolac; nabumetane; piroxicam; celecoxib;rofecoxib; meloxicam; JTE-522; L-745,337; NS398; and pharmaceuticallyacceptable salts thereof. The most preferred analgesic is naproxen. Thisshould be present at between 50 mg and 1500 mg and preferably at between200 and 600 mg. Although any form of naproxen is compatible with theinvention, naproxen sodium is generally preferred.

More generally, the present invention encompasses pharmaceuticalcompositions in unit dosage form that contain at least one analgesic(preferably an NSAID) in combination with metoclopramide and which areeither coordinated or in which at least one analgesic is long acting orformulated to be long acting. In all cases, the combination of drugsshould be effective to reduce or eliminate headache pain. Long actingNSAIDs suitable for use in the dosage forms include: ibuprofen;flurbiprofen; ketoprofen; oxaprozin; etodolac; indomethacin; ketorolac;nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam; JTE-522;L-745,337; NS398; or pharmaceutically acceptable salts thereof Whennaproxen, the preferred analgesic, is used, it should be present in anamount of between 50 and 1500 mg and preferably between 200 and 600 mg.The sodium salt of naproxen is generally preferred. Analgesics that maybe formulated to be long acting include ibuprofen, aspirin andacetaminophen. Methods for making appropriate long acting formulationsfor these and other analgesics are well known in the art (see, e.g.,Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, EastonPa. (1980); Controlled Drug Delivery, 2nd rev. and ex. ed., Joseph R.Robinson & Vincent H. L. Lee eds., Marcel Dekker (1987), ISBN:0824775880; Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz,John Wiley & Sons (1999), ISBN: 0471148288). Coordinated dosage formsshould be suitable for oral delivery and will typically take the form ofa tablet or capsule. Metoclopramide and NSAID may be in separate layersof a multilayer tablet and, in general, these dosage forms should besubstantially free of vasoactive agents such a 5 HT agonists.

Pharmaceutical compositions containing analgesics (e.g., long-actingNSAIDs or NSAIDs formulated to be long acting) may be acid-base storagestabilized or coordinated and should, preferably, be suitable for oraladministration (e.g. in the form of a tablet of capsule). It will alsogenerally be advantageous for metoclopramide to be present at aconcentration effective to reduce or eliminate the nausea associatedwith migraine headaches.

The present invention is also directed to methods of treating patientsfor migraine headaches. This may be accomplished by administering anamount of any of the dosage forms described above effective to reduce oreliminate one or more of the symptoms associated with a migraine attack.More generally, patients maybe administered metoclopramide inconjunction with an analgesic. A sufficient amount of these drugs shouldbe given so that, in combination, they reduce or eliminate headache.Preferably, patients should not be administered vasoactive agents suchas 5 HT agonists. Long-acting analgesics and analgesics formulated to belong acting may be used in the method. NSAIDS that can be used include:acetaminophen (when formulated to be long acting); ibuprofen;flurbiprofen; ketoprofen; naproxen; oxaprozin; etodolac; indomethacin;ketorolac; nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam;JTE-522; L-745,337; NS398; or pharmaceutically acceptable salts thereofIn general, naproxen is the most preferred NSAID, particularly when inthe form of naproxen sodium.

In addition, the invention encompasses methods of increasing the rate ofabsorption of a drug into the bloodstream of a patient by administeringit together with metoclopramide in a coordinated dosage form. Asdescribed above, the metoclopramide should be released first in anamount effective to increase gastric motility. A therapeuticallyeffective amount of the drug should then be released and reach thegastrointestinal tract of the patient during the period thatmetoclopramide is having its effect. For the purposes of this inventionabsorption is defined as the time from which the drug is administereduntil the time that it reaches a peak plasma concentration. Thistreatment will be particularly effective in patients suffering fromconditions associated with gastric stasis. For example, as suggestedfrom the above discussion, migraine patients may be administeredanalgesics. Typically, analgesics will be administered, with long-actingNSAIDs and particularly naproxen being preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. is a diagrammatic side view of a single layer dosage form of theinvention.

FIG. 2. is a diagrammatic side view of a bilayer dosage form of theinvention.

FIG. 3. is a diagrammatic side view of another bilayer dosage form ofthe invention.

FIG. 4. is a comparative dissolution plot of the metoclopramidepresented in a tablet coating layer and presented in a compressed tabletlayer.

FIG. 5a is a plot of plasma concentrations of metoclopramide uponadministration of tablet(s) of the present invention as disclosed inTablet Example 4.

FIG. 5b is a plot of plasma concentrations of naproxen sodium uponadministration of tablet(s) of the present invention as disclosed inTablet Example 4.

FIG. 6 is a diagrammatic cross section side view of a tablet coating panwith baffles and spray nozzles.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based upon the discovery of several improvedpharmaceutical compositions for administering analgesics, particularlyNSAIDs, to migraine patients. The first of these involves a unit dosageform that has metoclopramide and a non-acidic analgesic. Themetoclopramide should be present in an amount of between 1 and 100 mgand preferably between 2 and 20 mg. It should also be “rapidlyavailable,” i.e. sustained release formulations of metoclopramide willbe generally undesirable. The formulation should typically be free ofvasoactive agents to avoid side effects and the analgesic used should benon-acidic to avoid the loss of activity that has been found to resultfrom prolonged contact between metoclopramide and acidic drugs, e.g.aspirin.

The effectiveness of a dosage form containing metoclopramide and anacidic analgesic may be maintained if the drugs do not have substantialdirect contact with one another. For example, either metoclopramide oran NSAID may be coated with material that serves as a barrier to preventinteraction or the drugs may be segregated into different layers of amultilayer tablet. Methods for producing “acid-base storage stabilized”dosage forms are described in the Examples section below. Such dosageforms may, of course, be used with non-acidic analgesics as well and,preferably, are devoid of vasoactive agents. The preferred analgesic isnaproxen at between 200 and 600 mg.

A dosage form may also provide for coordinated delivery, i.e., deliveryin which there is the sequential release of metoclopramide followed byanalgesic. Again, methods for producing this type of dosage form aredescribed below. Coordinated dosage forms in which metoclopramide isused to promote drug absorption from the GI tract may also be used toadminister agents other than analgesics and will be particularly usefulfor treating diseases or conditions associated with gastric stasis.

Because migraine attacks are often prolonged, dosage forms having longacting analgesics, preferably, long acting NSAIDS, are greatlypreferred. For example, naproxen (with a half life of 12-15 hours) andoxaprozin (with a half-life of about 42 to 50 hours) are particularlywell suited for the treatment of migraine patients. Alternatively,analgesics may be specially formulated to be long acting.

Features of the dosage forms described above may, if desired becombined. For example, an acid-base stabilized dosage form may also becoordinated and contain a long acting NSAID. In all cases, it ispreferred that formulations for the treatment of patients be free fromvasoactive agents and that they be suitable for oral administration.

Making of Pharmaceutical Preparations

The pharmacologically active compositions of the invention can be madein accordance with methods that are standard in the art (see, e.g.,Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, EastonPa. (1980)). Drugs and drug combinations will typically be prepared inadmixture with conventional excipients. Suitable carriers include, butare not limited to: water; salt solutions; alcohols; gum Arabic;vegetable oils; benzyl alcohols; polyethylene glycols; gelatin;carbohydrates such as lactose, amylose or starch; magnesium stearate;talc; silicic acid; viscous paraffin; perfume oil; fatty acid esters;hydroxymethylcellulose; polyvinyl pyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and, if desired, mixed with auxiliaryagents, such as: lubricants; preservatives; stabilizers; wetting agents;emulsifiers; salts for influencing osmotic pressure; buffers; coloringagents; flavoring agents; and/or aromatic substances.

For non-parenteral applications, particularly suitable dosage forms aretablets, dragees, liquids, drops, suppositories, and capsules.Sublingual and buccal forms may also be used. Sustained or directedrelease compositions can be formulated, in which the active componentsare protected with differentially degradable coatings, e.g., bymicroencapsulation, multiple coatings, etc. It is also possible tofreeze-dry compositions and use the lyophilizates for the preparation ofproducts for injection.

Generally, the compositions of this invention will be dispensed in aunit dosage form comprising about 2-30 mg of metoclopramide and about200-1000 mg of naproxen sodium or equivalent doses of other NSAIDs in apharmaceutically acceptable carrier. Dosages for a given patient can bedetermined using methods well known in the art.

The Making of Tablet Dosage Forms

The combination of metoclopramide and an analgesic may take place in asingle layer tablet or other solid dosage form. A bi- or multi layertablet of the type described in this invention relieves nausea, improvesgastrointestinal motility which enhances the speed of absorption of theNSAID, and provides an enhanced therapeutic effect against migrainesymptoms in patients.

In a bilayer configuration, one portion of the tablet containsmetoclopramide in the required dose and appropriate excipients, agentsto aid dissolution, lubricants, fillers, etc., and is, preferably,designed to dissolve to 90% completion in the stomach in less than about10 minutes, thus increasing gastrointestinal motility and controllingnausea. The effect of the rapid availability of metoclopramide is toaccelerate delivery of the naproxen (or other analgesic) to the smallintestine which is the site of most rapid absorption. In a bilayertablet embodiment, the second portion of the tablet will contain,preferably, naproxen sodium in the required dose and appropriateexcipients, agents to aid dissolution, lubricants, fillers, etc. Itshould generally dissolve up to 90% completion after the metoclopramideportion has dissolved and within about 60 minutes.

In one embodiment of bilayer tablet preparation, once the two componentshave been manufactured, they are combined into a single tablet. Thisprocess allows for different dosages of either component (i.e. themetoclopramide component or the naproxen sodium component) to beusefully combined into a single tablet in an efficient way. In anotherembodiment, substantially each naproxen sodium crystal (ormetoclopramide particle) is coated with a rapid dissolving excipientmaterial, conveniently, prior to tableting.

Powder flow characteristics and powder compressibility are the maincriteria to be considered with respect to successful tablet production.To improve compressibility, naproxen sodium may be granulated. Thisinvolves increasing granule size through the addition of excipients thatprovide binding properties as well as disintegration properties.Granulation methods can be performed in a dry or wet state and include:“slugging;” low- or high-shear granulation; wet granulation; and,fluidized-bed granulation. Of these processes, slugging generallyproduces tablets of less hardness and greater friability. Low-sheargranulation, high-shear granulation, wet granulation and fluidized-bedgranulation generally produce harder, less breakable tablets.

Useful dosages of other analgesics to combine with metoclopramideinclude aspirin (particularly about 325-1000 mg and 500-650 mg),phenacetin, and acetaminophen (particularly about 325-1000 mg). Suchanalgesics may be formulated to be long acting or may be in acoordinated dosage form. In cases where the analgesic is acidic (e.g.aspirin), acid base stabilized dosage forms should be used, e.g., theacidic analgesic and the metoclopramide may be sequestered to differentlayers of a multilayer tablet in such a manner that contact between thedrugs is eliminated or minimized. In the case of COX-2 inhibitors, thenon-acidic analgesic Celecoxib (Celebrex®) is particularly useful whencontained in tablets of from about 100 to 200 mg. Celecoxib peak plasmaconcentrations occur approximately 3 hours after oral dosing. Theeffective half-life is approximately 11 hours.

Definitions

A. “Long acting” in relation to NSAIDs and other analgesics shall mean apharmacokinetic half-life of at least about 2 hours and preferably 8-14hours. Particular preferred analgesics are flurbiprofen with a half-lifeof about 6 hours; ketoprofen with a half-life of about 2 to 4 hours;naproxen ((+(s)-6-methoxy-α-methyl-2-naphthaleneacetic acid) andnaproxen sodium with half-lives of about 12 to 15 hours and about 12 to13 hours respectively; oxaprozin with a half-life of about 42 to 50hours; etodolac with a half-life of about 7 hours; indomethacin with ahalf-life of about 4 to 6 hours; ketorolac with a half-life of up toabout 8-9 hours; nabumetane with a half-life of about 22 to 30 hours;mefenamic acid with a half-life of up to about 4 hours; and piroxicamwith a half-life of about 4 to 6 hours. If an analgesic does notnaturally have a half life sufficient to be long acting, it can be madelong acting by the way in which it is formulated.

B. “Therapeutically effective amount” shall mean the dosage of drug thatprovides the specific pharmacological response for which the drug isadministered in a significant number of subjects in need of suchtreatment. It is emphasized that migraine headache is not wellunderstood and the etiology of particular migraines vary, as does theresponse to particular drugs. Thus reference to “specificpharmacological response for which the drug is administered in asignificant number of subjects in need of such treatment” is arecognition that a “therapeutically effective amount,” administered to aparticular subject in a particular instance will not always abort amigraine attack or relieve an actual migraine headache, even though suchdosage is deemed “therapeutically effective” by those skilled in theart. It is to be further understood that drug dosages are, in particularinstances, measured as oral dosages, or parenteral or inhaled dosages orwith reference to drug levels as measured in blood.

Metoclopramide hydrochloride monohydrate is conveniently provided inconventional tablets of 5 and 10 mg, as a solution of 5 mg/5 ml and asan injectable solution of 5 mg/ml. Although metoclopramide is notrecognized by the FDA as an effective agent for the treatment ofmigraine, practitioners find doses of at least 10 mg by injection i.m.or intravenously to be useful for the treatment of the nauseaaccompanying migraine. Oral doses of 10-20 mg are less useful because ittakes longer for therapeutic blood levels to be reached, resulting in aslower onset of action.

Dosages of analgesics will be adjusted by physicians based upon clinicalfactors. Nevertheless, some generalizations can be made. Indomethacinshould be useful when present in tablets in a range of from about 25 to75 mg, when present in suppositories at about 50 mg, and when in oralsuspensions at a concentration of about 25 mg/5 ml. A typical daily oraldosage of indomethacin is three 25 mg doses taken at intervals duringone day. However, daily doses of up to about 150 mg are also useful insome subjects. Sustained release dosage forms of indomethacin are alsoavailable and provide longer lasting blood levels than conventionaltablets. In particular, a 25 mg sustained release dosage form can beused as an alternative to 25 mg three times daily or 75 mg twice dailycan be substituted for 50 mg three times daily.

Ibuprofen is conveniently provided in tablets or caplets of 50, 100,200, 300, 400, 600, and 800 mg and as a suspension of 100 mg/5 ml. Dailydoses should not exceed 3200 mg and doses should be individualized. 200mg-800 mg may be particularly useful when given 3 or 4 times daily.

Flurbiprofen is useful when in tablets at about 50 to 100 mg. Dailydoses of about 100 to 500 mg, and particularly about 200 to 300 mg totalare usually effective.

Ketoprofen is particularly useful when contained in capsules in anamount of about 25 to 75 mg. Daily doses of about 100 to 500 mg, andparticularly about 100 to 300 mg are useful, as is about 25 to 50 mgevery six to eight hours.

Naproxen is particularly useful when contained in tablets of from 250 to500 mg, and in oral suspensions of about 125 mg/5 ml. For naproxensodium, tablets of about 275 or about 550 mg are particularly useful.Initial doses of about 100 to 1250 mg, and particularly 350 to 800 mg,are also useful with doses of about 550 mg being generally preferred.

Oxaprozin is notable for having a pharmacokinetics half-life of 42-50hours and a bioavailability of 95%. It is usefully provided as capletsof 600 mg. Daily doses of 1200 mg have been found to be particularlyuseful and daily doses should not exceed 1800 mg or 26 mg/kg. The lowesteffective dose should always be used.

Etodolac is usefully provided in capsules of 200 mg and 300 mg and intablets of 400 mg. Useful doses for acute pain are 200-400 mg every 6-8hours, not to exceed 1200 mg/day. Patients weighing less than 60 kg areadvised not to exceed doses of 20 mg/kg. Doses for other uses are alsolimited to 1200 mg per day in divided doses, particularly 2, 3, or 4times daily.

Ketorolac is usefully provided in tablets of 10 mg and as a sterileparenteral preparation for injection in 15 mg/ml and 30 mg/ml dosageforms. Oral doses of up to 40 mg, and particularly 10-30 mg per day andparenteral doses up to 120-150 mg per day have been useful in theamelioration of pain.

Nabumetane may be provided in tablets of between 500 mg and 750 mg.Daily doses of 1500-2000 mg/day after an initial dose of 1000 mg are ofparticular use.

Mefenamic acid is particularly useful when contained in capsules ofabout 250 mg. For acute pain such as migraine, an initial dosage of 1 to1000 mg and particularly about 500 mg is useful, though other dosagesmay be required for specific subjects.

Meclofenamate sodium is provided as capsules of 50 mg and 100 mg. Dailydoses of up to 400 mg may be used. Typically a patient will take 50-100mg every 4-6 hours.

One particular group of long acting NSAIDs that may be used are thecyclooxygenase-2 (“COX-2”) inhibitors, for example: celecoxib,rofecoxib, meloxicam, piroxicam, JTE-522, L-745,337, or NS398, orpharmaceutically acceptable salts thereof. JTE-522, L-745,337 and NS398are described, inter alia, in Wakitani, et al., Jpn. J. Pharmacol.78:365-371 (1998); and Panara, et al., Br. J. Pharmacol. 116:2429-2434(1995). The amount present in a tablet or administered to a patient willdepend upon the particular COX-2 inhibitor being used. For example,piroxicam may be present at 10 to 20 mg per tablet. Celecoxib may beadministered to a human in an amount of from about 100 mg to about 500mg or preferably, in an amount of from about 100 mg to about 200 mg.

D. “Effective local gastrointestinal concentration” shall be understoodto mean a dosage of metoclopramide that produces local improvement ingastric motility, with particular reference to the pyloric sphincter insubjects undergoing a migraine attack. While displaying variance fromsubject to subject, effective local gastrointestinal concentrationsexhibit a peak blood level of from about 1 to about 150 ng/ml in 20minutes.

E. “Co-timely” as to metoclopramide/analgesic combination drug therapyshall mean administration of an analgesic while metoclopramide ispresent or becomes present, in an effective local gastrointestinalconcentration. In a preferred embodiment of co-timely drugadministration, both drugs are administered in a single oral unit dosageform.

F. “Coordinated” in the practice of the present invention refers to thesequential administration of metoclopramide and at least one drug,preferably an NSAID, wherein the metoclopramide is available in aneffective concentration at the gastrointestinal tract of the subjectwithin 1 to 30 minutes after administration (preferably in 5 minutes orless and, more preferably, in 3 minutes or less). At least one analgesicshould be initially available at a therapeutically effective level in 5to 60 minutes after administration. The therapeutically effective levelof the analgesic should not be attained until after metoclopramide ispresent at an effective local gastrointestinal concentration.

To establish the sequential dissolution of dosage forms, standard USPdissolution methods and apparatus are useful. In humans, the peak bloodlevels of naproxen sodium produced by the invention often occur at least15-30 minutes more quickly than with standard USP tablets of naproxensodium. Furthermore, migraine symptom relief will occur statisticallymore quickly and more often than with standard USP tablets of naproxensodium.

The time to peak plasma levels for particular NSAIDs is as follows:flurbiprofen peaks in about 1 to 2 hours; ketoprofen peaks in aboutone-half to 2 hours; naproxen and naproxen sodium peak at about 2 to 4hours and 1 to 2 hours respectively; oxaprozin peaks at about 3 to 5hours; etodolac peaks at about 1 to 2 hours; indomethacin peaks at about1 to 4 hours; ketorolac peaks at about one-half to 1 hour; nabumetanepeaks at about 2.5 to 4 hours; mefenamic peaks at about 2 to 4 hours;meclofenamate peaks in 0.5-1 hours; and piroxicam peaks at about 3 to 5hours.

G. “Rapid availability” as to metoclopramide in an oral dosage formshall be understood to be essentially the complete solubilization ofmetoclopramide from the dosage form within 30 minutes and preferablywithin 5 minutes from ingestion. Clearly, an oral dosage form ofmetoclopramide which is liquid at the time of administration would alsorepresent a “rapid availability” form.

H. “Non-vasoactive” shall mean the substantial absence of demonstrateddirect activity (either dilation or constriction) at therapeutic doseson either local or systemic arterial or venous blood vessels. Migraineattacks are associated with dilation of blood vessels in the head, andrelief of a migraine headache has been associated with a reduction ofsuch vasodilation.

I. “5 HT agonist vasoactive agents” refers to a class of 5 HT agonistswith selective or non-selective vasoactivity on blood vessels includingsumatriptan and all compounds either structurally and/orpharmacologically similar to it, ergotamine and all compounds eitherstructurally and/or pharmacologically similar to it, and other serotoninagonists that exert a vasoactive effect. Metoclopramide, while havingminimal 5 HT agonist activity is excluded from the definition of 5 HTvasoactive agents because of its insignificant activity on blood vesselsat therapeutic doses.

“Ergots” refers to derivatives of 6-methylergoline. This includes formswith a substituent in the β configuration at position 8 and a doublebond in ring D. Particular note is made of the amide derivatives ofd-lysergic acid, a group of compounds which contain a double bondbetween C9 and C10. Many pharmaceutically active members of this classcontain a methyl or hydroxymethyl group at position number 8, and aretermed clavine alkaloids. Additional note is made of ergocornine,ergocristine, α-ergocryptine and β-ergocryptine, and ergonovine.Synthetic derivatives include dihydroergotamine, dihydroergocristine,bromocriptine, the amides of lysergic acid (such as lysergic aciddiethylamide, and lysergic acid hydroxybutamide). Also included areproducts of the methylation of the indole nitrogen of lysergic acidhydroxybutamide, which is methysergide. “Serotonin agonists” refers todrugs which bind to and stimulate serotonin receptors (e.g., 5 HT−1, 5HT−2 etc.).

J. “Migraine,” unless otherwise specified, will be understood to includethe subset of headaches characterized by unusually severe, unilateral,throbbing, headache pain, usually persisting for 4-72 hours and oftenincluding one or more of the following symptoms: nausea, vomiting,sensitivity to light or sound. Migraines are sometimes preceded by an“aura” and visual “scotoma.”

K. “Supra-vasoactive syndrome” or SVS shall mean that grouping ofadverse reactions and clinical findings generally thought to be due toexcessive vasoactivity remote from the intended site of action. SVScomprises one or more of the following symptoms and clinical findings:elevated blood pressure; reduced blood pressure; increased or reducedheart rate; cold extremities; tingling; flushing; feelings of neck orchest pressure, tightness, or heaviness; dizziness; hot or burningsensations; muscle pains; discomfort in the extremities; and frankangina or discomfort of cardiac origin. Thus, “SVS-minimized” shall meanthe substantial absence of SVS upon administration of an therapeuticallyeffective amount of an anti-migraine preparation.

L. “Initial migraine relief” shall be understood to be the reduction orabolition of migraine symptoms during the first few hours of an attackand particularly during the first 6 hours.

M. “Relapse headache” variously and interchangeably termed a “rebound,”“relapse,” “recurrent,” “follow on,” or “secondary” headache shall meanheadaches experienced by migraine patients after having experiencedinitial relief. A relapse headache may occur during the next 1 to 24hours.

N. “Unit dosage form” shall mean single drug administration entity. Byway of example, a single tablet, capsule, dragee, or trochee (oral unitdosage forms), suppository, or syringe combining both metoclopramide andan NSAID would be a unit dosage form. Administration of the unit dosageform will result in blood levels of the NSAID required to produce atherapeutic effect within about the first hour after dosing and willstill be present at least about 8-12 hours after initial dosing, and inparticular instances, for as long as about 24 hours after dosing. Bloodlevels of the metoclopramide establishing effective localgastrointestinal concentration will be present within the first hour andshould persist in measurable quantities for at least about 2-6 hours.

A particular type of unit dosage form is an “acid-base storage stable”unit dosage form. “Acid-base storage stable” unit dosage form shall meana unit dosage form of metoclopramide (a Lewis base, whether in the formof a free base or as an acid salt) and analgesic in which the potency ofeither active ingredient is not reduced by more than about 15% in 21days storage at ambient temperature (15-20 degrees C.), or by more thanabout 5% in 14 days. Acidic analgesic drugs are well known in the artand are exemplified by aspirin. A “non-acidic analgesic” is a compoundthat has a pK_(a) of 7 or above when dissolved in water, e.g.,celecoxib, pK_(a)=11.1

A “uniform-coated unit dosage form” shall mean a unit dosage formwherein the coating containing metoclopramide remains unchanged withinthe limits of between 85% and 115% with a relative standard deviation ofno more than about 6.4.

O. “Enhanced therapeutic effect” in the context of this invention shallmean that the initial relief of migraine symptoms will occur morequickly and/or more extensively with the combination of two agentscompared to the same doses of each component given alone, or that lessthan standard doses of one or both components can be combined to providerelief of migraine symptoms at least comparable in speed and extent tothat achieved with standard doses of either agent.

While the experienced clinician is able to monitor and adjust dosagesfor each subject relative to the severity of the migraine attack and thepresence of side-effects, generally available information on maximumcommon daily dosages of NSAIDs is useful as a guideline. In particularinstances, however, exceeding these “maximum” doses is the therapeuticchoice of the medical professional. Maximum daily doses in milligrams isas follows: flurbiprofen 300; ketoprofen 300; naproxen 1500, naproxensodium 1375; oxaprozin 1800; etodolac 1200; indomethacin 150 to 200;ketorolac 120 mg i.m. and 40 oral; nabumetane 2000; mefenamic acid 1000;and piroxicam 20.

P. “Non-spiking” metoclopramide peaks shall mean a plasma concentrationof metoclopramide which remains within the limit of variation of itsmean value for two or more consecutive time points. As seen in FIG. 5,administration of unit dosage forms of the present invention producednon-spiking peak circulating levels of metoclopramide. The data wasobtained from 10 healthy volunteer subjects. On day 1, the subjects wereadministered one tablet of 500 mg naproxen sodium and 8 mgmetoclopramide prepared as described in the Examples section. On day 4,two such tablets were administered. Venous blood samples were collectedin Li⁺ heparin tubes at the times shown. Red and white cells were thenseparated, and the supernatant deproteinated. The supernatant was thenassayed for naproxen and metoclopramide and validated with referencestandard by 40 times recrystallization.

Q. “High stability” in reference to sustained metoclopramide plasmalevels shall mean less than a 10% deviation (post-t_(max)) from the meanover a 15 minute period within 6 hours of administration. Without beingbound by any particular theory, it is believed that by combiningmetoclopramide with an analgesic, and particularly a long-acting NSAID,one can achieve an enhanced therapeutic effect within the first 6 hoursafter dosing and a lower incidence of relapse headaches for the first24-48 hours. Furthermore, this effect may be achievable with less thanstandard doses of one or both of these therapeutic agents. For example,the combination of less than standard doses of metoclopramide andnaproxen sodium may result in fewer gastrointestinal complications suchas bleeding, ulceration, dyspepsia, heartburn, constipation, anddizziness, drowsiness, and headache due to naproxen sodium and lesssomnolence, agitation, restlessness, fatigue, and extrapyramidalsymptoms including involuntary movements of the limbs, facial grimaces,torticollis, etc. due to the metoclopramide.

EXAMPLES Example 1 Tablet Formulation #1

A variety of combinations of metoclopramide and analgesic can be madeinto a single dosage form (e.g., tablet, capsule, suppository)consisting of one or more layers. In this example, a sequentially andrapidly dissolving single layer tablet of metoclopramide, 8 mg, iscombined with naproxen sodium, 500 mg. Referring to FIG. 1, this singlelayer tablet contains naproxen sodium in crystalline form (2) andmetoclopramide (4), each uniformly distributed throughout a matrix (6)of pharmaceutically acceptable fillers, excipients, binding agents,disintegrants, and lubricants (collectively, “carrier material”). Apharmaceutically acceptable tablet coating (8) surrounds the activeingredients and carrier materials. Carrier material should be present inan amount of between 50 and 2000 mg, and preferably between 500 and1,000 mg. Prior to compaction in a tablet, each crystal of naproxensodium may optionally be coated with excipient. Tablets may includemicrocrystalline cellulose and magnesium stearate. For example, naproxensodium may be coated with hydroxypropyl methylcellulose 2910 andpolyethylene 8000. A core bulking agent such as lactose may be used inpreparations together with a polymer film coating such as Opaspray®K-1-4210A or Opadry® YS- 1-4215 (trademarks of Colorcon, West Point,Pa.). Povidone and talc may also be used as bulking agents for thetablet core.

Tablet stability is compromised in instances in which there is an“acid-base incompatibility” between the metoclopramide and theanalgesic. For example, naproxen sodium (the more easily absorbed formof analgesic) is a crystalline solid that is freely soluble in water ofneutral pH. Metoclopramide hydrochloride is also freely soluble inwater. The basic salt of metoclopramide intimately mixed with acidicnaproxen sodium crossreacts in a matter of days causing reduction intablet potency of about 5% in two weeks and about 20 to 25% or more inthree weeks at ambient temperature. Thus, separation between thecomponent active ingredients is advantageous and can be achieved byincluding either or both active ingredients in barrier coated form.Suitable barrier coating materials for naproxen sodium include OpaDry asapplied in combination with water for irrigation and talc. Othermaterials are shellac, hydroxypropyl methylcellulose phthalate,polyvinyl acetate phthalate, and cellulose acetate phthalate. Thincoatings, on the order of about 25-250 microns, retard the availabilityof naproxen by no more than about 5 minutes, while substantiallyextending storage life of the combined formulation.

Example 2 Tablet Formulation #2

FIG. 2. depicts a sequentially and rapidly dissolving bilayer tablet ofmetoclopramide, 16 mg, combined with naproxen sodium 500 mg. The tabletconsists of a first layer (11) and a second layer (13). The first layer(11) contains naproxen sodium in crystalline form (12) uniformlydistributed throughout a matrix (16) of pharmaceutically acceptablefillers, excipients, binding agents, disintegrants, and lubricants(collectively, “first carrier material”). The second layer (13) containsmetoclopramide (14) uniformly distributed throughout a matrix (17) ofpharmaceutically acceptable fillers, excipients, binding agents,disintegrants, and lubricants (collectively, “second carrier material”).A pharmaceutically acceptable tablet coating (18) surrounds the activeingredients and carrier materials. Dotted line 15 represents theinterface between the two layers which are separately molded, poured,compressed or otherwise formed and joined by compression or other tabletforming means. The first carrier material and the second carriermaterial may be either the same or different.

In one embodiment, the metoclopramide portion may be in effervescentformulation which, upon addition to water, becomes a liquid, and theNSAID, e.g., naproxen, remains in solid form. Tablets may be in the formof a single lozenge, or may form numerous coated beads or granules (withparticular reference to sizes within the 4 to 12 sieve range) acting asa slurry in the effervescent solution. A number of tableting techniquesare described in Pharmaceutical Dosage Forms and Drug Delivery Systems,Ansel et al., Sixth Ed. (Williams & Wilkins, Media Penn., 1995) theteachings of which are incorporated herein by reference.

Example 3 Tablet Formulation #3

A particular example of a tablet in which metoclopramide is in aneffervescent matrix separated from analgesic is as follows:

A. Metoclopramide: Metoclopramide in the form of an acid salt isprepared in a particle size of from about 4 to 10 mesh size (4.76 mm to2.00 mm) formed by moistening blended powders and passing them through ascreen or granulator. In this manner, 60 mg of metoclopramide arecombined with 250 gm of a mixture of: 200 gm dried dibasic sodiumphosphate; 477 gm sodium bicarbonate in dry powder; 252 gm tartaric acidin dry powder; and 162 gm citric acid monohydrate.

B. Naproxen: 500 mg of naproxen sodium are compacted as granules with:povidone k-29/32 (23.6 mg); microcrystalline cellulose, NF (105.9 mg);croscarmellose sodium, NF, (13.5 mg); talc (27 mg); and magnesiumstearate (5 mg).

C. The metoclopramide granules and the naproxen are combined into atwo-layer tablet as described in Example 2.

Example 4 Tablet Formulation #4

FIG. 3. depicts another example of a sequentially and rapidly dissolvingbilayer tablet in which metoclopramide hydrochloride (8 mg) is combinedwith naproxen sodium (500 mg). Referring to the figure, the bilayertablet consists of a first layer (311) and a second layer (313) havingan exterior portion (317) and an interior portion (319). The first layer(311) contains naproxen sodium granules in crystalline form (312)uniformly distributed throughout a matrix (316) of pharmaceuticallyacceptable fillers, excipients, binding agents, disintegrants, andlubricants (collectively, “first carrier material”), to form a core. Thesecond layer (313) contains metoclopramide hydrochloride in crystallineform (314) uniformly distributed throughout the exterior portion oflayer (313), wherein (317) comprises a matrix of pharmaceuticallyacceptable tablet coating. A tablet coating (317) surrounds both thesecond layer as well as the layer of naproxen and carrier material(311). Dotted line (315) represents the interface between the exteriorportion (313) and the interior portion (319). This interface maycomprise titanium dioxide, camauba wax, shellac, cellulose acetatephthalate or the like. Interior portion (319) may comprise about 2 to 3%of the coating material of (313) and separates the naproxen layer orcore from the metoclopramide. As depicted diagrammatically in FIG. 3,the portion of the coating layer below line (315) is comprised of thesame coating material as matrix (317). This architecture separates theacidic naproxen from the basic form of metoclopramide.

The naproxen-containing portion of tablets may be separately molded,poured, compressed or otherwise formed and joined by compression orother tablet forming means. It is then spray coated with a materialabsent metoclopramide, e.g., HPMC, triethyl citrate, and TiO2 applied inan aqueous spray. Coatings of 1 to 10%, and preferably 2 to 3%, of thetotal coating weight are useful. Later, a second spray coating whichincludes metoclopramide hydrochloride is applied and serves to furthersegregate metoclopramide from naproxen. A preferred second coatingcomprises: HPMC (35 to 55%, preferably 42 to 47% and most preferablyabout 45%); titanium dioxide (3 to 8%, preferably 4 to 6% and mostpreferably about 5%); triethylcitrate (0.05 to 0.3%, preferably 0.07 to0.2% and most preferably about 0.1%); talc (17% to 35%, preferably 21 to27% and most preferably about 24%; and metoclopramide (10 to 40%,preferably 20 to 30% and most preferably about 26%). The metoclopramidehydrochloride may be suspended in coating solution that is applied to acore consisting of about 100-1000 mg of naproxen sodium, and preferablyabout 500 mg.

Preparation of a tablet of FIG. 3 requires particular attention to theapplication of metoclopramide in such a manner as to maintain acceptabletablet dosage uniformity (“uniform-coated unit dosage form”). Coatingshould be uniform to between 85% and 115% of the intended dosage with arelative standard deviation of 6.4 or less. With pancoating methodology,it is important to control pan speed, movement of tablets across thetablet bed, spray temperature and spray coverage relative to the entirepan. Tablets sticking to each other or to the pan during coating willreduce uniformity. Thus, it is advantageous to apply a coating materialthat does not readily stick to the pan, and to agitate tablets(“agitating rotation”) during coating such that tablets do not stick toeach other. Employing a coating pan with baffles offers agitatingrotation of the tablets being coated. A coating that does not causetablets to stick to each other during agitating rotating in a coatingpan is termed an “adhesion reduced” coating. An example of an additivethat may be used to produce an adhesion reduced coating is talc (atleast 18%, preferably at least 20% and most preferably at least 24% ofthe dry weight of the metoclopramide-containing outer portion).

FIG. 6 depicts an apparatus for coating tablets. A rotating coating pan(602) is partially filled with tablet cores to be coated. In theembodiment shown, screen panels (604) facilitate air circulation, andbaffles (608) placed on the coating pan walls agitate tablet coresduring rotation. Spray nozzles ((612) and (614)) leading from a spraymixture reservoir, and pump means spray coating through an inlet (610)over tablet cores. An air source (618) introduces drying air into thecoating pan from a heating and pumping source (not shown). Air exitsthrough a vacuum outlet (620) as well as through screen panels (604).The coating pan is agitated by a rotating means (622).

A preferred method of making tablets is to coat NSAID cores,particularly naproxen cores, with an atomized coating mixture while thecores are in a rotating pan. Although not limited to any particularapparatus, suitable devices are the Driacoater/Vario 500/600 (Driam USA,Spartanburg, Pa.) and spray guns such as the 460 Bink spray gun (BinksManufacturing Company, Franklin Park Ill.)). Using two spray guns about10 to 12 inches apart and 4 to 8 inches above the tablet bed shouldproduce a suitable coating when pans are rotated at a speed of 14 to 16rpm. It is particularly important to maintain tablet movement in the panto avoid tablet sticking and enhance coating uniformity.

Example 5 Tablet Formulation #5 (Metoclopramide Film Coated Tablet)

This acid-base storage stable uniform-coated unit dosage form hasmetoclopramide as a film in the outermost portion of the tablet andseparated from the naproxen sodium. The final tablet formulation byweight is as follows:

A. metoclopramide hydrochloride 8 mg (i) metoclopramide-containingcoating (in percentage of total metoclopramide containing coating dryweight) hydroxypropyl methylcellulose 45% ± 5%  titanium dioxide 5% ± 2%triethyl citrate 0.1% ± 0.5% metoclopramide 26% ± 1%  talc 24% ± 1% (ii) metoclopramide free coating (in percentage of total tablet dryweight) hydroxypropylmethylcellulose 9% titanium dioxide 1% triethylcitrate 2% B. naproxen core naproxen sodium 500 mg povidone k-29/32 23.6mg microcrystalline cellulose, NF, 105.9 mg croscarmellose sodium, NF13.5 talc 27 mg magnesium stearate 5 mg

To prepare a two layer tablet as in FIG. 3., particular attention ispaid to the application of the film coating. Naproxen cores are placedin the coating pan with baffles in place and with a rotation speed ofabout 14-16 rpm. From two spray guns mounted about 4 to 8 inches apartand 10 to 12 inches above the tablet bed, atomized metoclopramide-freecoating mixture is sprayed over the rotating pan until the coresincrease from about 2% to about 3% in weight. Continuous drying isperformed by air input at about 65° C.±5°, and with an exhausttemperature of 45° C.±5°. Spraying pressure when the atomizer is set at2.0-4.0 yields a spray particle size of about 10 μm to about 200 μm andaveraging about 50 μm.

After the initial coating step, tablets are again spray coated in therotating baffled pan, but now with a metoclopramide-containing coatingmaterial until the tablet weight increases from about 8 to about 10%over the weight of the naproxen core. For example, sufficient sprayingmay be performed to apply 8 mg of metoclopramide to each tablet.

After spraying is complete, tablets are examined for uniformity inkeeping with the requirement of a “uniform-coated unit dosage form.”Testing the content of metoclopramide HCl should confirm that themetoclopramide in the coating of each tablet is between 85% and 115% ofthe calculated dosage with a standard deviation of no more than 6.4.

Example 6 Examination of Tablet Dissolution Time

A comparison of dissolution times was made between unit dosage forms.Dissolution was determined by USP apparatus #2 for which, 70-80%represents essentially total dissolution (unless stirrer speeds aremarkedly increased). Data is presented in FIG. 4 for:

(i) naproxen sodium and metoclopramide HCl, each in a separate layer butwith the metoclopramide in a coating film (see Example 5)

(ii) naproxen sodium and metoclopramide HCl in a single matrix notacid-base stable, but newly made; and

(iii) naproxen sodium and metoclopramide HCl in a single matrix notacid-base stable, after 14 days storage at ambient temperature (15°-20°C.).

Essentially complete solubilization of metoclopramide from the oraldosage form was observed within about 5 minutes (using 0.01 M to 0.1 MHCl) for the tablet of Example 4.

Example 7 First Treatment Example

An adult female migraineur complains of a migraine attack with typicalsymptoms: headache, nausea and sensitivity to light and sound. She isadministered a single oral (single layer) tablet containingmetoclopramide (8 mg) and naproxen sodium (250 mg). Her symptoms startto diminish within one hour and, by three hours, she is completelysymptom free. No relapse over the next 48 hours is reported.

Example 8 Second Treatment Example

An adult female migraineur complains of a migraine attack with typicalsymptoms: migraine headache, nausea and sensitivity to light and sound.She is administered a single oral (bilayer) tablet containingmetoclopramide (16 mg) and naproxen sodium (500 mg). Her symptoms startto diminish within one hour. By three hours, she is completely symptomfree and has no relapse over the next 48 hours.

Example 9 Third Treatment Example

The same symptoms as in the patients of Example 7 and 8 are presented bya male, 25 years of age. Upon oral administration of a single layertablet containing 16 mg of metoclopramide and 1000 mg naproxen sodiumthe same result is obtained.

The metoclopramide and NSAID combined compositions of this and theprevious examples may conveniently be prepared at several unit dosageform strengths, e.g., 8 mg metoclopramide/500 mg naproxen sodium; 16 mgmetoclopramide/500 mg naproxen sodium; 8 mg metoclopramide/250 mgnaproxen sodium; 16 mg metoclopramide/250 mg naproxen sodium.

Example 10 Fourth Treatment Example

An adult female migraineur complains of a migraine attack consisting oftypical symptoms: headache, nausea and sensitivity to light and sound.She is administered a tablet prepared according to Example 5 containingmetoclopramide (8 mg) and naproxen sodium (500 mg). The naproxen movesfrom the stomach into the duodenum within 5 minutes of dosing. Hersymptoms start to diminish within one hour and by three hours she iscompletely symptom free. No relapse occurs over the next 48 hours.

Example 11 Clinical Study of Pharmacokinetics

The absorption and elimination kinetics of a single dose of ametoclopramide/naproxen preparation, “MT 100,” (16 mg metoclopramidehydrochloride and 500 mg naproxen sodium) was compared to naproxensodium alone (500 mg); metoclopramide hydrochloride alone (16 mg); andtwo tables of MT 100 in a randomized, four-period, cross-over Phase Istudy. Twenty-four healthy volunteers (14 females and 10 males), aged20-55 years, received each of the four treatments. Blood samples fordetermination of plasma concentrations of naproxen and metoclopramidewere collected at the following times: 0, 10, 20, 30, 40, 50, 60, 75 and90 minutes, and 2, 4, 6, 12, 24, 48 and 72 hours post dosing. Standardpharmacokinetic parameters were calculated, including maximum plasmaconcentrations over the entire sampling phase (Cmax), time to attainmaximal plasma concentrations (Tmax), and area under the plasmaconcentration-time curve (AUCI-time 0 to infinity).

For metoclopramide, dose proportionality was shown in comparing thekinetics (AUCI and Cmax) of a single dose of MT 100 with 2 tablets of MT100 (see Table 1 below). Time to maximal concentration was unchangedbetween doses. Cmax and AUCI were slightly less than dose proportionalfor naproxen concentrations. This finding is likely due to increasedclearance at the higher dose of MT 100, as naproxen is known to behighly protein bound and renal elimination can increase once bindingsites have been saturated.

TABLE 1 Pharmacokinetic of a Single Dose of MT 100 and 2 Tablets of MT100 MT 100 (1 tab) MT 100 (2 tabs) PK Parameter MC¹ NAP² MC¹ NAP² AUCI[μg*hr/mL] 643 1292 1278 1934 Cmax [μg/mL] 58.4 96.9 116.1 151.6 Tmax[hr] 1.32 0.72 1.36 0.80 ¹Metoclopramide ²Naproxen

As a result of its gastric pro-kinetic effects, it was expected thatmetoclopramide might speed the absorption of naproxen when the two weredelivered together in the coordinated-release MT 100 dosage form. Asshown in Table 2, this was demonstrated based on a comparison of plasmanaproxen levels for a single MT 100 tablet vs. those for the tabletcontaining naproxen sodium alone. The presence of metoclopramideresulted in an earlier Tmax (by approximately 30 minutes) and a slightlyhigher maximal plasma naproxen concentration.

TABLE 2 Pharmacokinetics of Naproxen in MT 100 Versus Naproxen Sodium PKParameter MT 100 Naproxen Sodium Cmax [μg/mL] 96.9 84.4 Tmax [hr] 0.721.20

The pharmacokinetics of MT 100 showed an increased Cmax for themetoclopramide and naproxen in the female subjects, with the Tmaxremaining relatively constant (Table 3).

TABLE 3 Pharmacokinetics of MT 100 by Gender NAP in MT 100 MC in MT 100(1 tab) (1 tab) PK Parameter Male Female Male Female Cmax [μg/mL] 88.8102.7 39.4 71.9 Tmax [hr] 0.75 0.70 1.20 1.40

In general, all doses of MT 100, naproxen and metoclopramide were welltolerated in this study.

Example 12 Phase III Clinical Study of Efficacy

One thousand sixty-four migraine patients participated in a phase III,randomized, single-dose, double-blind, parallel group study designed tocompare the safety and efficacy of MT 100 (16 mg metoclopramidehydrochloride and 500 mg naproxen sodium) versus its individualcomponents of naproxen sodium (NAP) and metoclopramide hydrochloride(MC). The randomization schedule was imbalanced by design and resultedin 422, 428, and 214 patients being treated with MT 100, NAP, and MC,respectively. The MC group functioned as the placebo group forcomparative purposes since MC was demonstrated in an earlier phase IIstudy to be without significant effect on pain variables.

Several measures were used to assess response, including “sustainedresponse,” defined as a reduction of moderate or severe pain to no painor only mild pain at 2 hours without a return to either moderate orsevere pain or the use of rescue medicine over the next 22 hours.“Complete response,” was also calculated and is defined in the same wayas sustained response with the exception that it ignores the use ofrescue medicine. Other measures included assessments of pain intensitydifferences (PID) and sum of pain intensity differences (SPID) at eachtime point, total pain relief (TOTPAR) at each time point, sustainedpain free status, response (reduction of moderate or severe pain to noor mild pain) at each time point, use of rescue medicines, nausea reliefand time to nausea relief, as well as assessments of other migrainesymptoms at each time point. Relapse, defined as the recurrence ofheadache pain to moderate or severe levels in patients who had attainedeither no or mild pain status at 2 hours, was also recorded.

MT 100 was superior to MC (placebo-equivalent) with respect to painrelief (PID, SPID, TOTPAR) beginning at one hour after dosing andcontinuing throughout the remainder of the 24 hour follow-up period. MT100 was also superior to MC as measured by the sustained response rate,complete response rate and the sustained pain free rate. MT 100 was alsosuperior to MC with respect to the 2 hour pain relief rate, pain freerate and for most other efficacy variables except those associated withnausea relief.

Compared to NAP, MT 100 was superior with respect to pain measures.Sustained response and complete response were higher for MT 100 than forNAP. The long lasting benefit of MT 100 over NAP was confirmed by thesuperiority of the MT 100 24 hour SPID score and 24 hour TOTPAR score.Consistent with its longer duration of action, there were significantlyfewer patients requiring rescue medicine, and the time to rescue wassignificantly longer in the MT 100 group. Fifty percent fewer 2 hourresponders with MT 100 had a return to either moderate or severe painscore within 22 hours compared to NAP. Additionally, greater nausearelief was seen at one hour with MT 100 vs. NAP as evidenced by highernausea relief scores.

Adverse events were uncommon and there appear to be no differences inthe incidence of any adverse events between groups. Only somnolence anddiarrhea were reported by more than 2% of patients in any treatmentgroup. In general, MT 100 was extremely well tolerated.

What is claimed is:
 1. A pharmaceutical composition in unit dosage formsuitable for oral administration in the treatment of migraine headache,comprising; (a) metoclopramide in an amount effective to increasegastric motility in a patient; and (b) a non-acidic analgesic in anamount effective to reduce or eliminate pain associated with saidmigraine headache; and wherein said unit dosage form is substantiallyfree of any 5 HT agonist vasoactive agent.
 2. A pharmaceuticalcomposition in unit dosage form suitable for oral administration in thetreatment of migraine headache, comprising: (a) metoclopramide in anamount effective to increase gastric motility in a patient; and (b) anon-acidic NSAID in an amount effective to reduce or eliminate painassociated with said migraine headache.
 3. The pharmaceuticalcomposition of claim 2, wherein said NSAID is a long acting NSAID. 4.The pharmaceutical composition of claim 2, wherein said NSAID is acyclooxygenase-2 inhibitor.
 5. A pharmaceutical composition in unitdosage form suitable for oral administration to a human for thetreatment of migraine headache, comprising: metoclopramide and naproxen,present in an amount such that the combination is effective in reducingor eliminating pain associated with said migraine headache and whereinsaid dosage form is an acid-base storage stabilized dosage form.
 6. Apharmaceutical composition in unit dosage form suitable for oraladministration to a human for the treatment of migraine headache,comprising: metoclopramide and an analgesic, present in an amount suchthat the combination is effective in reducing or eliminating painassociated with said migraine headache and wherein said dosage form iscoordinated.
 7. The pharmaceutical composition of claim 6, wherein saidunit dosage form is a tablet or capsule.
 8. The pharmaceuticalcomposition of claim 7, wherein said metoclopramide and said analgesicare in separate layers of a multilayer tablet.
 9. The pharmaceuticalcomposition of claim 6, wherein said unit dosage form is substantiallyfree from any 5 HT agonist vasoactive agent.
 10. The pharmaceuticalcomposition of claim 6, wherein said analgesic is an NSAID.
 11. Thepharmaceutical composition of claim 10, wherein said NSAID is selectedfrom the group consisting of: acetaminophen; ibuprofen; flurbiprofen;ketoprofen; naproxen; oxaprozin; etodolac; indomethacin; ketorolac;nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam; JTE-522;L-745,337; and NS398; or a pharmaceutically acceptable salt thereof. 12.The pharmaceutical composition of claim 11, wherein said NSAID isnaproxen.
 13. The pharmaceutical composition of claim 10, wherein saidNSAID is long acting or is formulated to be long acting.
 14. A method ofincreasing the rate of absorption of a drug into the bloodstream of apatient, wherein rate of absorption is the time from which the drug isadministered until the time that it reaches a peak plasma concentration,comprising: administering said drug together with metoclopramide in acoordinated dosage form, wherein said metoclopramide is administered inan amount effective to increase gastric motility and wherein said drugis administered in a therapeutically effective amount.
 15. The method ofclaim 14, wherein said patient is in a state of gastric stasis at thetime said drug and said metoclopramide are administered.
 16. The methodof claim 14, wherein said drug is administered for the treatment ofmigraine headache.
 17. The method of claim 14, wherein said drug is ananalgesic.
 18. The method of claim 14, wherein said drug is an NSAID.19. The method of claim 18, wherein said NSAID is long acting or isformulated to be long acting.
 20. The method of claim 18, wherein saidNSAID is selected from the group consisting of: acetaminophen;ibuprofen; flurbiprofen; ketoprofen; naproxen; oxaprozin; etodolac;indomethacin; ketorolac; nabumetane; piroxicam; celecoxib; rofecoxib;meloxicam; JTE-522; L-745,337; and NS398; or a pharmaceuticallyacceptable salt thereof.
 21. The method of claim 20, wherein said NSAIDis naproxen.
 22. A pharmaceutical composition in unit dosage formsuitable for oral administration in the treatment of migraine headache,comprising: (a) metoclopramide in an amount effective to increasegastric motility in a patient; and (b) a non-acidic analgesic in anamount effective to reduce or eliminate pain associated with saidmigraine headache; and wherein said unit dosage form is coordinated. 23.The pharmaceutical composition of claim 22, wherein said unit dosageform is a tablet or capsule.
 24. The pharmaceutical composition of claim22, wherein said unit dosage form is substantially free of any 5 HTagonist vasoactive agent.
 25. The pharmaceutical composition of claim22, wherein said analgesic is a long acting NSAID.
 26. Thepharmaceutical composition of claim 22, wherein said analgesic is acyclooxygenase-2 inhibitor.
 27. The pharmaceutical composition of claim26, wherein said cyclooxygenase-2 inhibitor is celecoxib.
 28. Thepharmaceutical composition of claim 27, wherein said celecoxib ispresent in an amount of between 25 and 250 mg and said metoclopramide ispresent in an amount of between 1 mg and 100 mg.
 29. The pharmaceuticalcomposition of claim 22, wherein said analgesic is formulated to be longacting.
 30. A pharmaceutical composition in unit dosage form suitablefor oral administration in the treatment of migraine headache,comprising: (a) metoclopramide in an amount effective to increasegastric motility in a patient; and (b) a non-acidic analgesic in anamount effective to reduce or eliminate pain associated with saidmigraine headache; and wherein said non-acidic analgesic is celecoxib.31. The pharmaceutical composition of claim 30, wherein said celecoxibis present in an amount of between 25 and 250 mg and said metoclopramideis present in an amount of between 1 mg and 100 mg.
 32. Thepharmaceutical composition of either claim 30 or claim 31, wherein saidunit dosage form is a tablet or capsule.
 33. The pharmaceuticalcomposition of either claim 30 or claim 31, wherein said unit dosageform is substantially free of any 5 HT agonist vasoactive agent.
 34. Apharmaceutical composition in unit dosage form suitable for oraladministration to a human for the treatment of migraine headache,comprising: metoclopramide and an analgesic, present in an amount suchthat the combination is effective in reducing or eliminating painassociated with said migraine headache and wherein said dosage form isan acid-base storage stabilized dosage form in which said metoclopramideand said analgesic are each in separate layers of a multilayer tablet.35. A pharmaceutical composition in unit dosage form suitable for oraladministration to a human for the treatment of migraine headache,comprising: metoclopramide and an analgesic, present in an amount suchthat the combination is effective in reducing or eliminating painassociated with said migraine headache, wherein said dosage form is anacid-base storage stabilized dosage form and wherein said unit dosageform is coordinated.
 36. The pharmaceutical composition of either claim34 or 35, wherein either said metoclopramide or said analgesic isbarrier coated.
 37. The pharmaceutical composition of either claim 34 or35, wherein said unit dosage form is substantially free of any 5 HTagonist vasoactive agent.
 38. The pharmaceutical composition of eitherclaim 34 or 35, wherein said analgesic is an NSAID.
 39. Thepharmaceutical composition of claim 38, wherein said NSAID is selectedfrom the group consisting of: acetaminophen; ibuprofen; flurbiprofen;ketoprofen; naproxen; oxaprozin; etodolac; indomethacin; ketorolac;nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam; JTE-522;L-745,337; and NS398; or a pharmaceutically acceptable salt thereof. 40.The pharmaceutical composition of claim 39, wherein said NSAID isnaproxen.
 41. The pharmaceutical composition of claim 38, wherein saidNSAID is long acting or is formulated to be long acting.